This invention relates to novel pentapeptides and, more particularly, to synthetic analogues of the naturally-occurring pentapeptides, Met-enkephalin and Leu-enkephalin.
It has recently been established that morphine and other opiates initiate their pharmacological effects by complexing reversibly with opiate receptors, which are stereo-specific components of vertebrate synaptic membranes distributed heterogeneously in the mammalian nervous system. A number of endogenous peptides which appear to serve as natural ligands for these opiate receptors, have been demonstrated to exist in brain, pituitary, human cerebrospinal fluid and human blood. The first of these natural ligands to be identified was extracted from porcine brain by Hughes et al. (Nature, Volume 258, Page 577, 1975) and termed "enkephalin," which was found to be a mixture of two pentapeptides having the formulas H-L-Tyr-Gly-Gly-L-Phe-L-Met-OH (Met-enkephalin) and H-L-Tyr-Gly-Gly-L-Phe-L-Leu-OH (Leu-enkephalin).
Both enkephalins when tested in vitro have been found to have a high affinity for opiate receptors, which is generally predictive of opiate potency in vivo. However, extremely high quantities of enkephalin (120-200 .mu.g) are required to elicit analgesia when microinjected into rat cerebral ventricles and brain. Thus, Met-enkephalin is at least 50-fold weaker than morphine as an analgesic despite the fact that it possesses about half of the affinity of morphine for rat brain opiate receptors. Moreover, Met-enkephalin's mild analgesia dissipates completely in several minutes, even when injected directly into active brain sites where morphine induces analgesia which persists for several hours. This apparent discrepancy between in vivo and in vitro potency is explained by the finding that enkephalin's affinity for opiate receptors is rapidly and efficiently destroyed by the action of body enzymes which cause degradation of the peptide bonds. Hence, due to its only very transient pharmacological effects, enkephalin has little, if any, potential therapeutic value.